The overall purpose of my research is to understand the role macrophages play in control an elimination of cancer in experimental animals and humans. Studies by me and others have investigated mechanisms by which in vitro macrophage tumoricidal activity can be enhanced (treatment with endotoxin, lymphocyte-derived activating factors, or mild oxidants) or depressed (treatment with lipoproteins, cortcosteroids, or red blood cells (rbc), hemoglobin (Hb), or iron). The potent inhibition caused by endocytosis of rbc, Hb, or iron is potentially important because it may help us understand mechanisms of macrophage activation and/or tumor cell killing, and because there are certain clinical states in which increased macrophage rbc catabolism and iron storage could be accompanied by depressed macrophage tumoricidal activity. The objectives of this proposal are: 1) to further characterize the molecular mechanisms by which rbc, Hb, and iron inhibit macrophage tumor cell killing in vitro, 2) to determine if in vivo alterations in rbc catabolism or iron status alters resistance to tumor growth or ability of macrophages to kill tumor cells in vitro, and 3) to determine if rbc, Hb, or iron alter human monocyte-macrophage tumor cytotoxicity in ways comparable to those noted for mouse macrophages.